Process for preparing azetidinone derivatives

ABSTRACT

A process for preparing an azetidinone derivative represented by the formula ##STR1## wherein R 1  represents a straight-chain or branched-chain lower alkyl group, substituted or unsubstituted aryl group, substituted or unsubstituted phenylmethyl group or substituted or unsubstituted phenyloxymethyl group, R 2  represents hydrogen atom, an optionally substituted hydrocarbon residue or protective group for amino group selected from the class consisting of acyl, silyl, sulfonyl and phosphonyl derived from organic or inorganic acid, and R 3  represents a substituted or unsubstituted aryl group or the residue of substituted or unsubstituted heterocyclic ring.

TECHNICAL FIELD

This invention relates to a process for preparing azetidinonederivatives and more particularly to a process for preparing azetidinonederivatives represented by the formula ##STR2## wherein R¹ represents astraight-chain or branched-chain lower alkyl group, substituted orunsubstituted aryl group, substituted or unsubstituted phenylmethylgroup or substituted or unsubstituted phenyloxymethyl group, R²represents hydrogen atom, an optionally substituted hydrocarbon residueor protective group for amino group selected from the class consistingof acyl, silyl, sulfonyl and phosphonyl derived from organic orinorganic acid, and R³ represents a substituted or unsubstituted arylgroup or the residue of substituted or unsubstituted heterocyclic ring.

The azetidinone derivatives of the formula (I) are important compoundsas intermediates for synthesizing cephalosporin-type antibiotics.

Conventional processes for preparing the azetidinone derivatives of theformula (I) include those which involve the reaction between thiol andsulfenic acid formed by thermal decomposition of penicillin sulfoxide,for example, the reaction of penicillin G-S-oxide with2-mercaptobenzothiazole [T. Kamizya et al., Tetrahedron Lett., 3001(1973)]. With this process, however, the amino-protecting group R² ofthe compound (I) is restricted by the substituents of the penicillinwhich is one of the reactants. Processes are known for synthesizing thecompounds (I) having various amino-protecting groups R² for amino whichprocesses comprise reacting a thiazolinoazetidinone derivative havingthe corresponding amino-protecting groups R² with a sulphenyl halide ina hydrous organic solvent [S. Torii et al., Tetrahedron Lett., 2495(1982)]. However, this process involves the preparation of a sulfenylhalide by reacting the corresponding disulfide or thiol with a halogensuch as chlorine or bromine and thus entails complicated reactionoperation. Further the process requires an excess amount of a sulfenylhalide because of its decomposition in a hydrous solution and involves acumbersome treatment for separating the decomposed sulfenyl halide. Forthese reasons, the process poses problems in terms of commercial massproduction.

We have conducted extensive research to develop a process usingdisulfide serving as an agent for converting the starting material tosulfenyl without employing halogen and found that the contemplatedcompound can be prepared by a simple procedure of reacting a compoundhaving the skeleton of 7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hepto-2-enewith an acid in a hydrous organic solvent in the presence ofdibenzothiazolyldisulfide. The invention has been accomplished based onthis novel finding.

DISCLOSURE OF THE INVENTION

This invention provides a process for preparing an azetidinonederivative represented by the formula ##STR3## wherein R¹ represents astraight-chain or branched-chain lower alkyl group, substituted orunsubstituted aryl group, substituted or unsubstituted phenylmethylgroup or substituted or unsubstituted phenyloxymethyl group, R²represents hydrogen atom, an optionally substituted hydrocarbon residueor amino-protecting group selected from the class consisting of acyl,silyl, sulfonyl and phosphonyl derived from inorganic or organic acid,and R³ represents a substituted or unsubstituted aryl group or theresidue of substituted or unsubstituted heterocyclic ring, the processcomprising reacting a thiazolinoazetidinone derivative represented bythe formula ##STR4## wherein R¹ and R² are as defined above with asulphur-containing compound represented by the formula

    R.sup.3 --S--Y                                             (III)

wherein R³ is as defined above and Y represents --SR³ or ##STR5## (inwhich R³ is as defined above and R⁴ and R⁵ each represent a cyclic oracyclic amine residue or imido residue) in the presence of an acid in ahydrous organic solvent.

The process of this invention eliminates the need to use a sulfenylhalide which requires special care in handling and gives thecontemplated compound in a high yield by carrying out a simple procedureunder mild conditions. This process facilitates the separation andpurification of the contemplated compound (I) and is significantlyadvantageous in feasibility of commercial mass production.

The starting compounds of the formula (II) to be used in the reaction ofthis invention can be any of the compounds having the skeleton of7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hepto-2-ene and possessingsubstituents which do not undergo undesired change when reacted underthe conditions of this invention. Examples of the groups represented byR¹ are methyl, ethyl, isopropyl, butyl, pentyl, hexyl and likestraight-chain or branched-chain lower alkyl groups; phenyl,p-nitrophenyl, p-chlorophenyl and like substituted or unsubstituted arylgroups; benzyl, p-nitrophenylmethyl, p-chlorophenylmethyl,p-methoxyphenylmethyl, diphenylmethyl and like substituted orunsubstituted phenylmethyl groups; phenoxymethyl, p-nitrophenoxymethyl,p-chlorophenoxymethyl and like substituted or unsubstitutedphenyloxymethyl groups; etc.

The atom represented by R² is hydrogen and examples of the groups R² areamino-protecting groups such as acyl, silyl, sulfonyl and phosphonylderived from inorganic or organic acid and optionally substitutedhydrocarbons, etc. Examples of acyl, silyl, sulfonyl, phosphonyl andlike amino-protecting groups derived from inorganic or organic acid areacetyl, propionyl, butyryl, trimethylsilyl, dimethylbutylsilyl,methanesulfonyl, ethanesulfonyl, phenylsulfonyl, p-toluenesulfonyl,diphenylphosphonyl, dibenzylphosphonyl, diethylphosphonyl, etc.Exemplary of the substituted hydrocarbons are those of the formulae##STR6##

In the formulae (IV) to (VII), R is hydrogen atom or carboxyl-protectinggroup, Z¹ and Z² are the same or different and are each hydrogen atom,halogen atom, sulphur group, oxygen group, nitrogen group or the likeand W is a protected hydroxyl group. Representative of thecarboxyl-protecting groups represented by R are benzyl, p-methoxybenzyl,trimethoxybenzyl, trimethoxydichlorobenzyl, piperonyl, diphenylmethyl,bis(p-methoxyphenyl)methyl, ditolylmethyl, phenyl-p-methoxyphenylmethyl,α-p-methoxyphenylethyl, α-p-methoxyphenyl-β-trichloroethyl,trichloroethyl, florenyl, tert-butyl, trityl, α-diphenylethyl, cumyl,p-nitrobenzyl, o-nitrobenzyl, o,p-dinitrobenzyl, phenacyl,p-bromophenacyl, 1-methoxycarbonyl-2-oxopropyl, methoxyethoxymethyl,methoxymethyl, benzyloxymethyl, isopropoxymethyl, etc. Examples of thesubstituents represented by Z¹ and Z² are bromine, chlorine, fluorineand like halogen atoms; methylthio, ethylthio, phenylthio,p-nitrophenylthio, pentachlorophenylthio, 2-pyridylthio,2-benzothiadiazolylthio, 1,3,4-thiadiazole-5-ythio,2-substituted-1,3,4-thiadiazole-5-ylthio, 1,2,3,4-tetrazole-5-ylthio,1-substituted-1,2,3,4-tetrazole-5-ylthio, o-ethyldithiocarbonate,N,N-diethyldithiocarbamate, phenylsulfonyl, p-methylphenylsulfonyl andlike sulphur groups; hydroxy, methoxy, ethoxy, acetoxy, benzoyloxy,nitrosoxy, nitryloxy, and like oxygen groups, dimethylamino,piperidine-1-yl and like nitrogen groups; etc. Examples of the protectedhydroxyl groups represented by W are diphenylphosphonyloxy,methanesulfonate, N-morphonyl, diphenylmethyloxy, etc.

The starting material (II) can be prepared by reacting the correspondingester of penicillin-1-oxide of the formula (VIII) with more than anequivalent of trimethylphosphorous acid with refluxing in benzene as asolvent, as shown below in a reaction equation or by further treatingthe reaction product resulting from the foregoing procedure according toa conventional method [S. Torii et al., Tetrahedron Lett., 3198 (1981)].##STR7##

Illustrative of the sulphur-containing compounds of the formula R³--S--Y (wherein R³ and Y are as defined above) which are used in thereaction of the invention are a disulfide wherein Y is --S--R³,sulfenamido wherein Y is ##STR8## and sulfenimido. Representative of thegroups R³ are phenyl, p-nitrophenyl, pentachlorophenyl and likesubstituted or unsubstituted aryl groups; 2-pyridyl, 2-benzothiazolyl,1,3,4-thiadiazole-5-yl, 2-methyl-1,3,4-thiadiazole-5-yl,1,2,3,4-tetrazole-5-yl, 1-methyl-1,2,3,4-tetrazole-5-yl,1-phenyl-1,2,3,4-tetrazole-5-yl, benzimidazole and like substituted orunsubstituted heterocyclic rings; etc. Examples of the groups ##STR9##are diethylamine, diisopropylamine and like primary or secondary amineresidues; cyclohexylamine, morpholine, piperidine, pyrrolidine, and likecyclic amine residues; phthalimido, succinimido and like imido residues;etc.

The ratio between the compound (II) and the compound (III) is notparticularly limited and accordingly can be suitably determined over awide range. The latter is used in an amount of usually about 1 to about10 moles, preferably about 1 to 2 moles, per mole of the former.

The reaction of this invention is conducted in a hydrous organic solventin the presence of an acid. The water content in the hydrous organicsolvent is not particularly restricted but is usually 1 to 1000equivalents, preferably about 10 to about 500 equivalents, relative tothe compound (II). Suitable organic solvents include, for example,pentane, hexane, benzene, toluene and like hydrocarbons; methylenechloride, chloroform, carbon tetrachloride, dichlorobenzene and likehalogenated hydrocarbons; methyl formate, methyl acetate, ethyl acetate,butyl acetate and like esters; diethyl ether, dimethyl ether,tetrahydrofuran, dioxane and like ethers; methanol, ethanol, butanol,ethylene glycol and like alcohols; formic acid, acetic acid, propionicacid and like carboxylic acids; acetonitrile, benzonitrile and likenitriles; dimethylformamide, dimethylacetamide and like amides;dimethylsulfoxide and like sulfoxides; nitromethane, nitroethane andlike nitrohydrocarbons; acetone, cyclohexane and like ketones; etc.These solvents are used singly or in mixture. Preferred examples ofuseful organic solvents are ethers, ketones, alcohols, amides,sulfoxides and like hydrophilic polar solvents or a mixture of otherclass of solvent and such hydrophilic solvent. The amount of thesolvent, although variable with the selection of the compounds (II) and(III), is usually 1 to 1000 parts, preferably 2 to 500 parts, per partof the compound (II).

Examples of useful acids are hydrogen halogenide, sulphuric acid, nitricacid, phosphoric acid, perchloric acid, chloric acid and like mineralacids; alkanesulfonic acid, arylsulfonic acid, aralkylsulfonic acid,α-haloalkanesulfonic acid and like sulfonic acids; α-halocarboxylicacid, polycarboxylic acid and like carboxylic acids; etc. among whichthose having a dissociation constant of about over 0.01 are preferred.Representative of such preferred acids are perchloric acid,trifluoroacetic acid, trichloroacetic acid, dichloroacetic acid,trifluoromethanesulfonic acid, trichloromethanesulfonic acid,hydrochloric acid, hydrobromic acid, sulphuric acid, hydrofluoric acid,nitric acid, phosphoric acid, benzenesulfonic acid, toluenesulfonicacid, etc. The amount of the acid, although variable with the selectionof the compounds (II) and (III) and the solvent, reaction temperatureand other conditions, is usually about 0.01 to about 50 moles,preferably about 0.1 to about 10 moles, per mole of the substrate.

When a side reaction is caused by the decomposition of an azetidinonering and an amino-protecting group R² and the like, the contemplatedcompound can be produced in high yields by appropriately determining theclass and concentration of the acid, reaction temperature, reaction timeand like conditions. The reaction of this invention rapidly proceeds ata temperature usually about 0° to about 50° C., preferably about 15° toabout 35° C., and is completed usually in about 5 minutes to 1 hour,whereby the contemplated compound can be produced in high yields.

The contemplated compound thus obtained is extracted and isolated in theusual manner after completion of the reaction, and can be easilypurified by conventional methods such as precipitation, filteration,recrystallization, chromatography or the like.

Of the present compounds of the formula (I), those wherein R¹ is astraight-chain or branched-chain lower alkyl, substituted orunsubstituted aryl, substituted or unsubstituted phenylmethyl, orsubstituted or unsubstituted phenyloxymethyl, R² is ##STR10## (in whichR is hydrogen or carbonyl-protecting group) and R³ is substituted orunsubstituted aryl or the residue of substituted or unsubstitutedheterocyclic ring are novel compounds undisclosed in literature.

The azetidinone derivatives prepared by the process of this inventioncan be each made into a cephalosporin-type antibiotic of the formula(IX) or (X), as indicated below in Reaction Equation-1 and ReactionEquation-2 (cf. Reference Example to be described later). ##STR11##

In Reaction Equation-1, R¹ R³ and R are as defined above and R⁶ is asubstituted or unsubstituted aryl, the residue of substituted orunsubstituted aromatic heterocyclic ring residue, thiocarboxylic acidresidue, thiocarbonic acid residue or thioamido residue. ##STR12##

In Reaction Equation-2, R¹, R and R³ are as defined above.

Given below are Examples and Reference Example for clarification of theinvention.

EXAMPLE 1 ##STR13##

Dispersed in 3 ml of tetrahydrofuran were 54.7 mg of methyl2-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hepto-2-ene-6-yl)-3-methyl-2-butenateand 72.0 mg of dibenzothiazolyldisulfide. To the dispersion was added0.75 ml of a 5% aqueous solution of hydrochloric acid and the mixturewas stirred at room temperature for 40 minutes. A 10 ml quantity ofethyl acetate was added to the reaction mixture and the insolubles wereremoved by a glass filter. The filtrate was washed with water and driedover anhydrous sodium sulfate. The solvent was distilled off to give133.3 mg of the residue, which was separated and purified by silica gelcolumn chromatography, affording 84.8 mg of methyl2-(4-(2-benzothiazolyl)dithio-3-phenylacetamide-2-oxoazetidine-1-yl)-3-methyl-2-butenateas white powder in about 100% yield.

IR (CHCl₃): 3400, 1770, 1720, 1672 cm⁻¹.

NMR (CDCl₃): δ(ppm) 2.07 (s, 3H), 2.12 (s, 3H), 3.57 (s, 3H), 3.66 (s,2H), 5.04 (dd, 1H, 5 Hz, 8 Hz), 5.38 (d, 1H, 5 Hz), 6.66 (d, 1H, 8 Hz),7.28 (s, 5H), 7.20-7.90 (m, 4H).

EXAMPLES 2 to 24 ##STR14##

Thiazolinoazetidinone (II) and disulfide (III) were dispersed intetrahydrofuran and an acid was added to the dispersion. The mixture wasstirred at room temperature for a predetermined period of time. Thereaction was conducted under the same conditions as Example 1 exceptthose as shown in Table 1 below, followed by the same post-treatment,whereby the contemplated azetidinone derivative (I) was produced.

Table 1 below shows the reaction conditions and yields and Table 2 belowindicates IR and ¹ HNMR data.

                                      TABLE 1                                     __________________________________________________________________________     Compound (II)             Compound (III)         Reaction                                                                            (I)                   Example                                                                            R.sup.1                                                                            R.sup.2         R.sup.3    (III/II)*                                                                          Acid    time (min.)                                                                         Yield                 __________________________________________________________________________                                                            (%)                   2    PhCH.sub.2                                                                          ##STR15##      Br         (1.24)                                                                             5% HCl  40    85                    3    PhCH.sub.2                                                                          ##STR16##      BT         (1.10)                                                                             10% HClO.sub.4                                                                        40    90                    4    PhCH.sub.2                                                                          ##STR17##      BT         (1.26)                                                                             1N H.sub.2 SO.sub.4                                                                   40    65                    5    PhCH.sub.2                                                                          ##STR18##      2-Py       (1.45)                                                                             5% HCl  40    75                    6    PhCH.sub.2                                                                          ##STR19##      2-Py       (1.26)                                                                             5% HCl  40    85                    7    PhCH.sub.2                                                                          ##STR20##      C.sub.5 Cl.sub.5                                                                         (1.20)                                                                             5% HCl  40    65                    8    PhCH.sub.2                                                                          ##STR21##      BI         (1.37)                                                                             5% HCl  40    55                    9    PhCH.sub.2                                                                          ##STR22##      BT         (1.36)                                                                             27% p-TsOH                                                                            40    98                    10   PhCH.sub.2                                                                          ##STR23##      BT         (1.08)                                                                             13% TFA 40    60                    11   PhOCH.sub.2                                                                         ##STR24##      BT         (1.40)                                                                             5% HCl  40    81                    12   PhCH.sub.2                                                                          ##STR25##      BT         (1.40)                                                                             5% HCl  35    99                    13   PhCH.sub.2                                                                          ##STR26##                                                                                     ##STR27## (1.32)                                                                             5% HCl  35    99                    14   PhCH.sub.2                                                                          ##STR28##      BT (1.06)  5% HCl                                                                             20      85                          15   PhCH.sub.2                                                                          ##STR29##      BT         (1.30)                                                                             5% HCl  40    90                    16   PhCH.sub.2                                                                          ##STR30##      BT         (1.30)                                                                             5% HCl  40    93                    17   PhCH.sub.2                                                                          ##STR31##      BT         (1.30)                                                                             5% HCl  40    92                    18   PhCH.sub.2                                                                          ##STR32##      BT         (1.30)                                                                             5% HCl  40    89                    19   PhCH.sub.2                                                                          ##STR33##      BT         (1.30)                                                                             5% HCl  40    88                    20   PhCH.sub.2                                                                          ##STR34##      BT         (1.32)                                                                             5% HCl  40    75                    21   PhCH.sub.2                                                                          ##STR35##      BT         (1.50)                                                                             5% HCl  40    80                    22   PhCH.sub.2                                                                          ##STR36##      BT         (1.10)                                                                             5% HCl  40    100                   23   PhCH.sub.2                                                                         H               BT         (1.06)                                                                             5% HCl  36    90                    24   PhCH.sub.2                                                                          ##STR37##      BT         (1.06)                                                                             5% HCl  40    85                    __________________________________________________________________________     Note:                                                                         ##STR38##                                                                     ##STR39##                                                                     TFA, trifluoroacetic acid; Et, ethyl.                                         *The mole of the compound (III) based on the mole of the compound (II)        (mole/mole).                                                             

                                      TABLE 2                                     __________________________________________________________________________    Compound (I)                                                                  R.sup.1                                                                             R.sup.2              R.sup.3                                            __________________________________________________________________________    PhCH.sub.2                                                                           ##STR40##                                                                                          ##STR41## IR (CHCl.sub.3) 3395, 1775, 1740,                                             1680 cm.sup.-1 NMR (CDCl.sub.3,                                               δ) 1.90 (s, 3H), 3.65 (s,                                               2H), 4.95 (s, 1H), 5.01 (s, 1H),                                              5.15(bs, 3H), 5.32 (dd, 1H), 4.5Hz,                                           8Hz), 5.53 (d, 1H, 4.5Hz), 6.46 (d,                                           1H, 8Hz), 7.28 (s, 5H), 7.30 (s,                                              5H), 7.20-8.00 (m, 4H)                  PhCH.sub.2                                                                           ##STR42##                                                                                          ##STR43## IR (CHCl.sub.3) 3400, 1770, 1735,                                             1670 cm.sup.-1 NMR (CDCl.sub.3,                                               δ) 1.88 (s, 3H), 3.63 (s,                                               2H), 4.87 (s, 1H), 4.99 (s, 1H),                                              5.12 (bs, 2H), 5.10-5.30 (m, 1H),                                             5.32 (s, 1H), 5.54 (d, 1H, 5Hz),                                              7.00-7.70 (m, 13H),  8.35 (m, 2H)       PhCH.sub.2                                                                           ##STR44##                                                                                          ##STR45## IR (CHCl.sub.3) 3390, 1770, 1720,                                             1678 cm.sup.-1 NMR (CDCl.sub.3,                                               δ) 1.98 (s, 3H), 2.15 (s,                                               3H), 3.58 (s, 3H), 3.65 (s, 2H),                                              5.22 (dd, 1H, 5Hz, 8Hz), 5.43 (d,                                             1H, 5Hz), 6.92 (d, 1H, 8Hz),                                                  7.00-7.80 (m, 7H), 8.30-8.50 (m,                                              2H)                                     PhCH.sub.2                                                                           ##STR46##                                                                                          ##STR47## IR (CHCl.sub.3) 3400, 1770, 1727,                                             1680 cm.sup.-1 NMR (CDCl.sub.3,                                               δ) 1.95 (s, 3H), 2.06 (s,                                               3H), 3.59 (s, 2H), 3.70 (s, 3H),                                              5.02 (dd, 1H, 5Hz, 8Hz), 5.53 (d,                                             1H, 5Hz), 6.38 (d, 1H, 8Hz), 7.26                                             (s, 5H)                                 PhCH.sub.2                                                                           ##STR48##                                                                                          ##STR49## IR (CHCl.sub.3) 3380, 3280, 1770,                                             1720, 1670 cm.sup.-1 NMR                                                      (CDCl.sub.3, δ) 1.97 (s, 3H),                                           2.20 (s, 3H), 3.58 (s, 3H), 3.72                                              (s, 2H), 4.76 (dd, 1H, 5Hz, 8Hz),                                             4.96 (d, 1H, 5Hz), 6.75 (d, 1H,                                               8Hz), 7.00-7.50 (m, 10H)                PhOCH.sub.2                                                                          ##STR50##                                                                                          ##STR51## IR (neat) 3320, 1775, 1735, 1675                                              cm.sup.-1 NMR (CDCl.sub.3, δ)                                           4.30 (s, 2H), 4.56 (s, 2H), 5.21                                              (s, 2H), 5.20-5.70 (m, 5H),                                                   6.70-8.00 (m, 15H)                      PhCH.sub.2                                                                           ##STR52##                                                                                          ##STR53## IR (neat) 3280, 1775, 1740, 1665                                              cm.sup.-1 NMR (CDCl.sub.3, δ)                                           2.62 (s, 3H), 3.60 (s, 2H), 4.21                                              (s, 2H), 5.16 (s, 2H), 5.05-5.40                                              (m, 3H), 5.46 (s, 1H), 5.55 (d, 1H,                                           4.5Hz), 7.05 (d, 1H, 8Hz), 7.25 (s,                                           5H), 7.30 (s, 5H)                       PhCH.sub.2                                                                           ##STR54##                                                                                          ##STR55## IR (neat) 3280, 1775, 1740, 1665                                              cm.sup.-1 NMR (CDCl.sub.3, δ)                                           3.66 (s, 2H),  4.15 and 4.89 (ABq,                                            2H, 11Hz), 5.14 (s, 2H), 5.00-5.40                                            (m, 3H), 5.50 (s, 1H), 5.55 (d, 1H,                                           4Hz), 6.92 (d, 1H, 8Hz), 7.10-7.60                                            (m, 12H), 7.60-8.00 (m, 2H)             PhCH.sub.2                                                                           ##STR56##                                                                                          ##STR57## IR (neat) 3280, 1780, 1745, 1670,                                             1235 cm.sup.-1 NMR (CDCl.sub.3,                                               δ) 2.00 (s, 3H), 3.64 (s,                                               2H), 4.70 (s, 2H), 5.11 (bs, 3H),                                             5.18 (dd, 1H, 5Hz, 8Hz), 5.25 (s,                                             1H), 5.46 (s, 1H), 5.48 (d, 1H,                                               5Hz), 6.63 (d, 1H, 8Hz), 7.10-7.60                                            (m, 12H), 7.60-8.00 (m, 2H)             PhCH.sub.2                                                                           ##STR58##                                                                                          ##STR59## IR (neat) 3280, 1780, 1740, 1670                                              cm.sup.-1 NMR (CDCl.sub.3, δ)                                           1.33 (t, 3H, 7Hz), 3.64 (s, 2H),                                              4.01 (s, 2H), 4.56 (q, 2H, 7Hz),                                              5.12 (s, 2H), 5.17 (s, 2H), 5.28                                              (dd, 1H, 4.5Hz, 8Hz), 5.46 (s, 1H),                                           5.50 (d, 1H, 4.5Hz), 6.76 (d, 1H,                                             8Hz), 7.10-7.60 (m, 12H), 7.60-8.00                                           (m, 2H)                                 PhCH.sub.2                                                                           ##STR60##                                                                                          ##STR61## IR (neat) 3300, 1780, 1745, 1670                                              cm.sup.-1 NMR (CDCl.sub.3, δ)                                           3.31 (bs, 3H), 3.39 (bs, 3H), 3.65                                            (s, 2H), 4.20 and 4.55 (ABq, 2H,                                              15Hz), 5.13 (s, 3H), 5.25 (s, 1H),                                            5.29 (dd, 1H, 4.5Hz, 8Hz), 5.50 (s,                                           1H), 5.52 (d, 1H, 4.5Hz), 6.76 (d,                                            1H, 8Hz), 7.20-7.60 (m, 12H),                                                 7.60-8.00 (m, 2H)                       PhCH.sub.2                                                                           ##STR62##                                                                                          ##STR63## IR (neat) 3270, 1780, 1740, 1670                                              cm.sup.-1 NMR (CDCl.sub.3, δ)                                           2.63 (s, 3H), 3.70 (s, 2H), 4.19                                              and 4.26 (ABq, 2H, 15Hz), 5.14 (s,                                            2H), 5.19 (s, 1H), 5.30-5.70 (m,                                              4H), 7.10-7.50 (m, 13H), 7.60-8.00                                            (m, 2H)                                 PhCH.sub.2                                                                           ##STR64##                                                                                          ##STR65## IR (neat) 3280, 1780, 1740, 1670                                              cm.sup.-1 NMR (CDCl.sub.3, δ)                                           3.68 (s, 2H), 4.30 (s, 2H), 5.07                                              (s, 2H), 5.17 (s, 1H), 5.26 (dd,                                              1H, 4.5Hz, 8Hz), 5.31 (s, 1H), 5.55                                           (d, 1H, 4.5Hz), 5.59 (s, 1H), 6.83                                            (d, 1H, 8Hz), 7.10-7.60 (m, 17H),                                             7.60-8.00 (m, 2H)                       PhCH.sub.2                                                                           ##STR66##                                                                                          ##STR67## IR (neat) 3280, 1780, 1740, 1670                                              cm.sup.-1 NMR (CDCl.sub.3, δ)                                           3.69 (s, 2H), 3.74 (s, 3H), 4.19                                              (bs, 2H), 5.10 (bs, 3H), 5.23 (dd,                                            1H, 4.5Hz, 8Hz), 5.36 (s, 1H), 5.48                                           (s, 1H), 5.57 (d, 1H, 4.5Hz), 6.79                                            (d, 1H, 8Hz), 7.10-7.60 (m, 12H),                                             7.60-8.00 (m, 2H)                       PhCH.sub.2                                                                           ##STR68##                                                                                          ##STR69## IR (CHCl.sub.3) 3390, 1785, 1720,                                             1670 cm.sup.-1 NMR (CDCl.sub.3,                                               δ) 3.68 (s, 2H), 4.68 (bs,                                              2H), 4.73 (bs, 2H), 4.84 (dd, 1H,                                             5Hz, 7Hz), 4.92 and 5.10 (ABq, 2H,                                            11Hz), 5.44 (d, 1H, 5Hz), 6.53 (d,                                            1H, 7Hz), 7.17 (s, 5H), 7.30 (s,                                              5H), 7.10-7.90 (m, 4H)                  PhCH.sub.2                                                                           ##STR70##                                                                                          ##STR71## IR (CHCl.sub.3) 3395, 1783, 1742,                                             1672 cm.sup.-1 NMR (CDCl.sub.3,                                               δ) 3.68 (s, 2H), 4.18 and                                               4.34 (ABq, 2H, 13Hz), 4.25 (bs,                                               2H), 4.99 (dd, 1H, 5Hz, 7.5Hz),                                               5.17 (s, 2H), 5.31 (s, 1H), 5.62                                              (d, 1H, 5Hz), 6.28 (d, 1H, 7.5Hz),                                            7.24 (bs, 5H), 7.30 (s, 5H),                                                  7.20-8.00 (m, 4H)                       PhCH.sub.2                                                                           ##STR72##                                                                                          ##STR73## IR (CHCl.sub.3) 3390, 3280, 1770,                                             1732, 1675 cm.sup.-1 NMR (CD.sub.3                                            COCD.sub.3, δ) 1.98 (s, 3H),                                            3.71 (s, 2H), 4.93 (s, 1H), 5.18                                              (bs, 2H), 5.32 (dd, 1H, 5Hz, 8Hz),                                            5.58 (d, 1H, 5Hz), 7.30 (s, 5H),                                              7.10-7.55 (m, 4H), 7.70-8.00 (m,                                              2H)                                     PhCH.sub.2                                                                          H                                                                                                   ##STR74## IR (nujol) 3280, 1790, 1670                                                   cm.sup.-1 NMR (CD.sub.3 SOCD.sub.3,                                           δ) 3.58 (bs, 2H), 5.20-5.30                                             (m, 2H), 7.23 (s, 5H), 7.00-7.60                                              (m, 2H), 7.60-8.00 (m, 2H), 9.10                                              (m, 2H)                                 PhCH.sub.2                                                                           ##STR75##                                                                                          ##STR76##  IR (neat) 3280, 1770, 1735, 1665                                             cm.sup.-1 NMR (CDCl.sub.3, δ)                                           2.70 (bs, 1H), 3.60 (s, 2H), 4.26                                             (s, 2H), 5.10 (s, 2H), 5.05-5.40                                              (m, 3H), 5.49 (d, 1H, 4Hz), 6.84                                              (d, 1H, 8Hz), 7.10-7.60 (m, 12H),                                             7.60-7.95 (m, 2H)                       __________________________________________________________________________     ##STR77##

Dispersed in 2 ml of tetrahydrofuran were 42.2 mg of methyl2-(3-phenyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hepto-2-ene-6-yl)-3-methyl-2-butenateand 50.2 mg of dibenzothiazolyldisulfide. To the dispersion was added0.5 ml of a 5% aqueous solution of hydrochloric acid and the mixture wasstirred at room temperature for 40 hours. After completion of thereaction, the same subsequent procedure as in Example 1 followed, giving53.7 mg of methyl2-(4-(2-benzothiazolyl)dithio-3-benzamido-2-oxo-azetidine-1-yl)-3-methyl-2-butenatein 80% yield.

IR (CHCl₃): 3410, 1772, 1722, 1664 cm⁻¹.

NMR (CDCl₃): δ(ppm) 2.18 (bs, 6H), 3.64 (s, 3H), 5.40 (dd, 1H, 5 Hz, 7Hz), 5.66 (d, 1H, 5 Hz), 7.15-8.00 (m, 10H). ##STR78##

Dispersed in 2 ml of methanol were 41.2 mg of methyl2-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hepto-2-ene-6-yl)-3-methyl-2-butenateand 46.5 mg of dibenzothiazolyldisulfide. A 0.5 ml quantity of a 5%aqueous solution of hydrochloric acid was added to the dispersion andthe mixture was stirred at room temperature for 40 minutes. The samesubsequent procedure as in Example 1 was conducted to provide 49.1 mg ofmethyl2-(4-(2-benzothiazolyl)dithio-3-phenylacetamide-2-oxo-azetidine-1-yl)-3-methyl-2-butenatein 75% yield. The product thus obtained was found identical in IR and ¹HNMR data with those of the compound produced in Example 1.

EXAMPLES 27 TO 30 ##STR79##

Reaction was conducted between methyl2-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hepto-2-ene-6-yl)-3-methyl-3-butenateand dibenzothiazolyldisulfide in solvents with the results as shown inTable 3 below. The reaction conditions other than those indicated inTable 3 were the same as Example 1. The compound (I) obtained was foundidentical in IR and ¹ HNMR data with the compound produced in Example 2.

                                      TABLE 3                                     __________________________________________________________________________       Compound (II)                                                                         Compound (III)          Time                                                                              (I)                                    Ex.                                                                              mg      R.sup.3BT mg                                                                          Solvent ml                                                                             5% HCl ml                                                                            (min)                                                                             Yield (%)                              __________________________________________________________________________    27 50.3    52.4    DMF    (3)                                                                             5% HCl  5  55                                                                 (0.8)                                             28 40.7    49.9    MeCN   (2)                                                                             5% HCl 55  63                                                                 (0.5)                                             29 40.5    46.9    MeOH   (2)                                                                             5% HCl 40  58                                                                 (0.5)                                             30 41.1    48.1    CH.sub.3 COCH.sub.3                                                                  (3)                                                                             .sub. 10% HClO.sub.4                                                                 40  94                                                        CH.sub.2 Cl.sub.2                                                                    (1)                                                                             (0.5)                                             __________________________________________________________________________     Note:                                                                         ##STR80##                                                                     DMF stands for demethylformamide; MeCN, acetonitrile; and MeOH, methanol.     ##STR81##

Dissolved in 2 ml of tetrahydrofuran were 41.1 mg of the compound (II)wherein R¹ is CH₂ Ph and R² is ##STR82## and 30.7 mg of the compound(III) wherein R³ is ##STR83## To the solution was added 0.5 ml of a 5%aqueous solution of hydrochloric acid and the mixture was stirred atroom temperature for 40 minutes. The reaction mixture was diluted withethyl acetate. The dilute was washed with a saturated aqueous solutionof sodium chloride and dried over anhydrous sodium sulfate. The solventwas distilled off. The resulting residue was separated and purified bysilica gel column chromatography, giving 46.4 mg of a compound (I)wherein R¹ is CH₂ PH, R² is ##STR84## and R³ is ##STR85## in 72% yield.The compound (I) thus obtained was found identical in IR and ¹ HNMR datawith the standard compound (I).

EXAMPLES 32 AND 33

Compounds (I) was prepared from compounds (II) and (III) by followingthe same procedure as Example 30. Table 4 below shows the results. Thecompounds (I) thus obtained were identical in IR and ¹ HNMR data withthe standard compound (I).

                  TABLE 4                                                         ______________________________________                                                            Compound (III)                                             Ex.  Compound (II)R.sup.1 R.sup.2                                                                 ##STR86##     Reac- tion time (Min.)                                                              (%)(I)                               ______________________________________                                        32   PhCH.sub.2                                                                             ##STR87##                                                                                ##STR88##  30    64                                  33   PhCH.sub.2                                                                             ##STR89##                                                                                ##STR90##  30    51                                  ______________________________________                                    

EXAMPLES 34 TO 57

The procedure of Example 1 was repeated, producing the compounds (I) asshown below in Table 5 which also indicates IR and ¹ HNMR data of thecompounds (I) thus obtained.

                                      TABLE 5                                     __________________________________________________________________________     ##STR91##                                            (I)                     Compound (I)                                                                  Ex.                                                                              R.sup.1                                                                            R.sup.2         R.sup.3   IR and .sup.1 HNMR Data                     __________________________________________________________________________    34 PhCH.sub.2                                                                          ##STR92##                                                                                     ##STR93##                                                                              IR (CDCl.sub.3) 3390, 1783, 1723, 1670                                        cm.sup.-1 NMR (400MHz, CDCl.sub.3,                                            δ) 3.38 (s, 3H), 3.75 (ABq, 2H,                                         16.4Hz), 4.24 and 4.84 (ABq, 2H,                                              12.6Hz), 4.45 and 5.10 (ABq, 2H,                                              14.0Hz), 4.95 (dd, 1H, 5.3Hz, 7.5Hz),                                         5.48 (d, 1H, 5.3Hz), 6.36 (d, 1H,                                             7.5Hz), 7.30 (s, 5H), 7.30-7.95 (m,                                           5H)                                         35 PhCH.sub.2                                                                          ##STR94##                                                                                     ##STR95##                                                                              IR (CHCl.sub.3) 3390, 1780, 1723, 1672                                        cm.sup.-1 NMR (CDCl.sub.3, δ)                                           3.39 (s, 3H), 3.68 (bs, 2H), 4.09 and                                         4.89 (ABq, 2H, 15Hz), 4.88 and 5.36                                           (ABq, 2H, 14Hz), 4.99 (dd, 1H, 5Hz,                                           8Hz), 5.46 (d, 1H, 5Hz), 6.77 (d, 1H,                                         8Hz), 7.10-8.10 (m, 19H)                    36 PhCH.sub.2                                                                          ##STR96##                                                                                     ##STR97##                                                                              IR (CHCl.sub.3) 3400, 1780, 1724, 1675                                        cm.sup.-1 NMR (CDCl.sub.3, δ)                                           1.40 (t, 6H, 7Hz), 3.56 (s, 3H), 3.74                                         (bs, 2H), 4.34 and 4.54 (ABq, 2H,                                             13Hz), 4.50 (bs, 2H), 4.67 (q, 4H,                                            7Hz), 5.13 (dd, 1H, 5Hz, 8Hz), 5.59 (d,                                       1H, 5Hz), 6.59 (d, 1H, 8Hz), 7.37 (s,                                         5H), 7.20-8.00 (m, 4H)                      37 PhCH.sub.2                                                                          ##STR98##                                                                                     ##STR99##                                                                              IR (CHCl.sub.3) 3390, 1778, 1720, 1672                                        cm.sup.-1 NMR (CDCl.sub.3, δ)                                           3.59 (s, 3H), 3.68 (s, 2H), 4.70 and                                          4.91 (ABq, 2H, 13Hz), 4.83 (bs, 2H),                                          5.17 (dd, 1H, 5Hz, 8Hz), 5.63 (d, 1H,                                         5Hz), 6.75 (d, 1H, 8Hz), 7.10-8.00 (m,                                        17H)                                        38 PhCH.sub.2                                                                          ##STR100##                                                                                    ##STR101##                                                                             IR (CHCl.sub.3) 3380, 1777, 1717, 1670                                        cm.sup.-1 NMR (CDCl.sub.3, δ)                                           3.63 (bs, 2H), 4.11 (d, 1H, 15Hz),                                            4.55-5.14 (m, 5H), 5.32 (d, 1H, 5Hz),                                         5.38 (d, 1H, 14Hz), 6.57 (d, 1H, 8Hz),                                        7.10-8.00 (m, 24H)                          39 PhCH.sub.2                                                                          ##STR102##                                                                                    ##STR103##                                                                             IR (CHCl.sub.3) 3380, 1778, 1714, 1669                                        cm.sup.-1 NMR (CDCl.sub.3, δ)                                           1.38 (t, 6H, 7Hz), 3.66 (bs, 2H), 4.44                                        and 4.48 (ABq, 2H, 13Hz), 4.50 (bs,                                           2H), 4.62 (q, 4H, 7Hz), 4.93 (dd, 1H,                                         5Hz, 8Hz), 4.74 and 5.08 (ABq, 2H,                                            12Hz), 5.45 (d, 1H, 5Hz), 6.59 (d, 1H,                                        8Hz), 7.15 (s, 5H), 7.30 (s, 5H),                                             7.10-7.90 (m, 4H)                           40 PhCH.sub.2                                                                          ##STR104##                                                                                    ##STR105##                                                                             IR (CHCl.sub.3) 3390, 1778, 1712, 1670                                        cm.sup.-1 NMR (CDCl.sub.3, δ)                                           3.56 (bs, 2H), 4.63 and 4.83 (ABq, 2H,                                        13Hz), 4.68 and 4.86 (ABq, 2H, 14Hz),                                         4.90 and 5.08 (ABq, 2H, 12Hz), 4.98                                           (dd, 1H, 5Hz, 8Hz), 5.48 (d, 1H, 5Hz),                                        6.62 (d, 1H, 8Hz), 7.10 (s, 5H), 7.23                                         (s, 5H), 7.00- 7.90 (m, 12H)                41 PhCH.sub.2                                                                          ##STR106##                                                                                    ##STR107##                                                                             IR (CHCl.sub.3) 3400, 1780, 1720, 1672                                        cm.sup.-1 NMR (CDCl.sub.3, δ)                                           3.73 (bs, 2H), 8.86 (s, 3H), 8.89 (s,                                         3H), 4.59 and 4.75 (ABq, 2H, 14Hz),                                           4.63 (bs, 2H), 4.92 (dd, 1H, 5Hz, 8Hz),                                       .99 and 5.13 (ABq, 2H, 12Hz), 5.48 (d,                                        1H, 5Hz), 7.17 (s, 5H), 7.32 (s, 5H),                                         7.20-7.99 (m, 5H)                           42 PhCH.sub.2                                                                          ##STR108##                                                                                    ##STR109##                                                                             IR (CHCl.sub.3) 3400, 1777, 1717, 1683                                        cm.sup.-1 NMR (CDCl.sub.3, δ)                                           2.70 (bs, 6H), 3.75 (bs, 2H), 4.50 and                                        4.73 (ABq, 2H, 13Hz), 4.50 and 4.87                                           (ABq, 2H, 14Hz), 4.98 and 5.13 (ABq,                                          2H, 12Hz), 5.40-5.60 (m, 2H), 7.10 (s,                                        5H), 7.10-7.90 (m, 10H)                     43 PhCH.sub.2                                                                          ##STR110##                                                                                    ##STR111##                                                                             IR (CHCl.sub.3) 3400, 1780, 1720, 1671                                        cm.sup.-1 NMR (CDCl.sub.3, δ)                                           3.57 (s, 3H), 3.72 (s, 2H), 4.62 and                                          4.78 (ABq, 2H, 10Hz), 4.70 (s, 2H),                                           4.97 (dd, 1H, 5Hz, 7Hz), 5.58 (d, 1H,                                         5Hz), 6.63 (d, 1H, 7Hz), 7.33 (s, 5H),                                        7.20-7.90 (m, 4H)                           44 PhCH.sub.2                                                                          ##STR112##                                                                                    ##STR113##                                                                             IR (CHCl.sub.3) 3350, 1775, 1721, 1670                                        cm.sup.-1 NMR (CDCl.sub.3, δ)                                           3.55 (s, 2H), 3.71 (s, 3H), 4.24 (bs,                                         2H), 5.18 (s, 1H), 5.20-5.50 (m, 3H),                                         5.48 (s, 1H), 7.00-7.70 (m, 8H), 8.40                                         (bd, 2H, 5.5Hz)                             45 PhCH.sub.2                                                                          ##STR114##     Ph        IR (CHCl.sub.3) 3380, 1770, 1730, 1680                                        cm.sup.-1 NMR (CDCl.sub.3, δ)                                           3.51 (s, 2H), 3.68 (s, 3H), 4.10 (bs,                                         2H), 4.94 (s, 1H), 5.11 (s, 1H),                                              5.20-5.50 (m, 3H), 6.12 (d, 1H, 8Hz),                                         7.10-7.60 (m, 10H)                          46 PhCH.sub.2                                                                          ##STR115##                                                                                    ##STR116##                                                                             IR (CHCl.sub.3) 3280, 1775, 1720, 1675                                        cm.sup.-1 NMR (CDCl.sub.3, δ)                                           2.70 (s, 3H), 3.66 (s, 2H), 3.79 (s,                                          3H), 4.26 (bs, 2H), 5.05-5.35 (m, 3H),                                        5.56 (s, 1H), 5.62 (d, 1H, 4.5Hz), 7.00                                       (d, 1H, 9Hz), 7.32 (s, 5H)                  47 PhCH.sub.2                                                                          ##STR117##                                                                                    ##STR118##                                                                             IR (CHCl.sub.3) 3390, 1770, 1735, 1658                                        cm.sup.-1 NMR (CDCl.sub.3, δ)                                           3.62 (s, 2H), 3.74 (s, 3H), 4.23 (bs,                                         2H), 5.14 (dd, 1H, 5Hz, 8Hz), 5.25 (s,                                        1H), 5.34 (s, 1H), 5.50 (s, 1H), 5.61                                         (d, 1H, 5Hz), 6.90 (d, 1H, 8Hz), 7.23                                         (s, 5H), 7.55 (bs, 5H)                      48 PhCH.sub.2                                                                          ##STR119##                                                                                    ##STR120##                                                                             IR (CHCl.sub.3) 3390, 1780, 1725, 1660                                        cm.sup.-1  NMR (CDCl.sub.3, δ)                                          3.60 (s, 2H), 3.77 (s, 3H), 3.97 (s,                                          3H), 4.24 (bs, 2H), 5.10 (dd, 1H, 5Hz,                                        8Hz), 5.21 (s, 2H), 5.47 (s, 1H), 5.66                                        (d, 1H, 5Hz), 7.04 (d, 1H, 8Hz), 7.26                                         (s, 5H)                                     49 PhCH.sub.2                                                                          ##STR121##                                                                                    ##STR122##                                                                             IR (CHCl.sub.3) 3390, 1785, 1730, 1670                                        cm.sup.-1 NMR (CDCl.sub.3, δ)                                           3.70 (s, 2H), 3.80 (s, 3H), 4.27 (bs,                                         2H), 5.17 (s, 1H), 5.25-5.45 (m, 3H),                                         5.61 (s, 1H), 6.72 (bd, 1H, 8Hz), 7.37                                        (s, 5H), 7.51 (d, 2H, 9Hz), 8.12 (d,                                          2H, 9Hz)                                    50 PhCH.sub.2                                                                          ##STR123##                                                                                    ##STR124##                                                                             IR (CHCl.sub.3) 3280, 1775, 1740, 1665                                        cm.sup.-1 NMR (CDCl.sub.3, δ)                                           3.69 (s, 3H), 4.16 and 4.40 (ABq, 2H,                                         12Hz), 5.21 (dd, 1H, 5Hz, 8Hz), 5.30                                          (bs, 2H), 5.53 (d, 1H, 5Hz), 5.56 (s,                                         1H), 7.02 (d, 1H, 8Hz), 7.20-7.60 (m,                                         7H), 7.55-7.95 (m, 2H)                      51 PhCH.sub.2                                                                          ##STR125##                                                                                    ##STR126##                                                                             IR (CHCl.sub.3) 3380, 1780, 1735, 1680                                        cm.sup.-1 NMR (CDCl.sub.3, δ)                                           3.65 (s, 2H), 4.22 (bs, 2H), 5.20 (s,                                         2H), 5.05-5.40 (m, 4H), 5.53 (s, 1H),                                         6.81 (bd, 1H, 8Hz), 7.34 (s, 10H), 7.42                                       (d, 2H, 9Hz), 8.05 (d, 2H, 9Hz)             52 PhCH.sub.2                                                                          ##STR127##                                                                                    ##STR128##                                                                             IR (neat) 3280, 1775, 1740, 1665                                              cm.sup.-1 NMR (CDCl.sub.3, δ)                                           2.62 (s, 3H), 3.60 (s, 2H), 4.21 (bs,                                         2H), 5.05-5.40 (m, 3H), 5.16 (s, 2H),                                         5.46 (s, 1H), 5.55 (d, 1H, 4.5Hz),                                            7.10-7.45 (m, 11H)                          53 PhCH.sub.2                                                                          ##STR129##                                                                                    ##STR130##                                                                             IR (neat) 3260, 1770, 1735, 1655                                              cm.sup.-1 NMR (CDCl.sub.3, δ)                                           3.55 (s, 2H), 4.24 (bs, 2H), 4.96 (s,                                         1H), 5.05-5.40 (m, 3H), 5.27 (s, 2H),                                         5.68 (d, 1H, 5Hz), 6.16 (d, 1H, 8Hz),                                         7.15-7.45 (m, 10H)                          54 PhOCH.sub.2                                                                         ##STR131##                                                                                    ##STR132##                                                                             IR (neat) 3310, 1780, 1745, 1685                                              cm.sup.-1 NMR (CDCl.sub.3, δ)                                           2.63 (s, 3H), 4.27 (bs, 2H), 4.58 (s,                                         2H), 5.24 (s, 2H), 5.20-5.60 (m, 4H),                                         5.70 (d, 1H, 5Hz), 6.70-7.60 (m, 11H)       55 PhOCH.sub.2                                                                         ##STR133##                                                                                    ##STR134##                                                                             IR (neat) 3300, 1775, 1740, 1680                                              cm.sup.-1 NMR (CDCl.sub.3, δ)                                           4.17 (bs, 2H), 4.38 (bs, 2H), 5.02 (s,                                        1H), 5.20 (s, 2H), 5.20-5.50 (m, 3H),                                         5.80 (d, 1H, 5Hz), 6.70-7.50 (m, 11H)       56 PhCH.sub.2                                                                          ##STR135##                                                                                    ##STR136##                                                                             IR (neat) 3160, 1770, 1735, 1650                                              cm.sup.-1 NMR (CDCl.sub.3, δ)                                           3.63 (s, 2H), 4.10 (s, 2H), 5.18 (s,                                          2H), 5.10-5.60 (m, 5H), 7.00-7.70 (m,                                         15H), 8.03 (bd, 1H, 6Hz)                    57 PhCH.sub.2                                                                          ##STR137##                                                                                    ##STR138##                                                                             IR (CHCl.sub.3) 3280, 1780, 1740, 1670,                                       640, 1270 cm.sup.- 1 NMR (CDCl.sub.3,                                         δ) 3.66 (s, 2H), 5.10 (s, 2H),                                          5.14 (s, 2H), 5.00-5.30 (m, 2H), 5.40                                         (s, 1H), 5.51 (d, 1H, 5Hz), 5.56 (s,                                          1H), 6.56 (d, 1H, 7.5Hz), 7.10-7.60 (m,                                       12H), 7.68-8.00 (m, 2H)                     __________________________________________________________________________

EXAMPLE 58 ##STR139##

Dispersed in 3 ml of tetrahydrofuran were 60 mg of benzyl2-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hepto-2-ene-6-yl)-3-methyl-3-butenateand 62 mg of 5,5'-dimethoxybenzothiazolyldisulfide. To the solution wasadded 0.75 ml of a 5% aqueous solution of hydrochloric acid and themixture was stirred at room temperature for 40 minutes.

To the reaction mixture was added 10 ml of ethyl acetate and theinsolubles were removed by a glass filter. The filtrate was washed withwater and dried over anhydrous sodium sulfate. The solvent was distilledoff.

The resulting residue was separated and purified by silica gel columnchromatography, giving 78.5 mg of benzyl2-(4-(5-methoxybenzothiazole-2-yl)dithio-3-phenylacetamide-2-oxo-azetidine-1-yl)-3-methyl-2-butenatein 87% yield.

NMR (CDCl₃): δ(ppm): 1.94 (s, 3H), 3.81 (s, 3H), 4.48 and 4.55 (ABq, 2H,J=1.25 Hz), 4.98 (s, 1H), 5.02 (s, 1H), 5.17 (s, 3H), 5.20-5.70 (m, 2H),6.70-7.60 (m, 14H).

EXAMPLES 59 TO 74

The procedure of Example 58 was followed to give the compounds (I) asshown in Table 6 below, which also indicates the yields and ¹ HNMR dataof the compound (I) thus obtained.

                                      TABLE 6                                     __________________________________________________________________________     ##STR140##                                                                   Ex. R.sup.1                                                                             R              R.sup.3        NMR (CDCl.sub.3, δ,                                                                        Yield              __________________________________________________________________________    59  PhOCH.sub.2                                                                          ##STR141##                                                                                   ##STR142##    1.98 (s, 3H), 4.59 (s, 2H), 5.01                                              (s, 1H), 5.04 (s, 1H), 5.19 (s,                                               2H), 5.22 (s, 1H), 5.45 (dd, 1H,                                              J=4.8 and 8.1Hz), 5.65 (d, 1H,                                                J=4.8Hz), 6.80-7.50 (m, 11H),                                                 7.85 (d, 1H, J=9.0Hz), 8.26 (dd,                                              1H, J=2.3 and 9.0Hz), 8.54 (d,                                                1H, J=2.3Hz)       89%                60  PhOCH.sub.2                                                                          ##STR143##                                                                                   ##STR144##    2.03 (s, 2H), 2.40 (s, 3H), 4.46                                              and 4.53 (ABq, 2H, J=12.5Hz),                                                 5.18 (s, 1H), 5.15-5.70 (m, 6H),                                              6.75-7.85 (m, 13H) 89%                61  PhOCH.sub.2                                                                          ##STR145##                                                                                   ##STR146##    1.95 (s, 3H), 2.67 (s, 3H), 2.87                                              (s, 6H), 3.94 (s, 2H), 4.46 and                                               4.53 (ABq, 2H, J=12Hz), 4.95 (s,                                              1H), 5.10 (s, 1H), 5.15 (s, 1H),                                              5.30-5.70 (m, 4H), 6.70-7.60 (m,                                              9H)                88%                62  PhOCH.sub.2                                                                          ##STR147##                                                                                   ##STR148##    1.94 (s, 3H), 3.82 (s, 9H), 4.51                                              (bs, 2H), 4.44 (s, 1H), 5.01 (s,                                              1H), 5.06 (s, 2H), 5.14 (s, 1H),                                              5.30-5.65 (m, 2H), 6.50 (s, 2H),                                              6.75-7.85 (m, 10H) 82%                63  PhOCH.sub.2                                                                          ##STR149##                                                                                   ##STR150##    1.93 (s, 3H), 3.75 (s, 3H),  4.50                                             (bs, 2H), 4.93 (s, 1H), 4.96 (s,                                              1H), 5.08 (s, 2H), 5.13 (bs, 1H),                                             5.42 (dd, 1H, J=4.0 and 6.5Hz),                                               5.56 (d, 1H, J=4Hz), 6.65-7.90                                                (m, 14H)           91%                64  PhOCH.sub.2                                                                          ##STR151##                                                                                   ##STR152##    1.96 (s, 3H), 4.58 and 4.52 (ABq,                                             H, J=12.5Hz), 5.04 (s, 1H), 5.20                                              (bs, 2H), 5.52 (dd, 1H, J=4.8 and                                             8.3Hz), 5.63 (d, 1H, J=4.8Hz),                                                6.79 (s, 1H), 6.80-7.90 (m,                                                                      83%)               65  PhOCH.sub.2                                                                         CH.sub.2 OCH.sub.3                                                                            ##STR153##    1.97 (s, 3H), 3.94 (s, 3H),                                                   4.49-4.54 (ABq, 2H, J=12Hz),                                                  4.75-5.25 (m, 5H), 5.45 (dd, 1H,                                              J=4.0 and 6.5Hz), 5.58 (d, 1H,                                                J=4.0Hz), 6.75-7.90 (m,                                                                          45%)               66  PhOCH.sub.2                                                                          ##STR154##                                                                                   ##STR155##    1.97 (s, 3H), 3.85 (s, 3H),                                                   2.35-3.60 (m, 2H), 3.60-3.85 (m,                                              2H), 4.54 (s, 2H), 4.75-5.75 (m,                                              7H), 6.75-7.90 (m,                                                                               53%)               67  PhCH.sub.2                                                                           ##STR156##                                                                                   ##STR157##    1.89 (s, 3H), 3.67 (s, 2H), 3.74                                              (s, 3H), 4.87 (s, 1H), 4.94 (s,                                               1H), 5.05 (s, 2H), 5.09 (bs, 1H),                                             5.25 (dd, 1H, J=4.0 and 7.0Hz),                                               5.45 (d, 1H, J=4.0Hz), 6.45 (d,                                               1H, J=7.0Hz), 6.55-7.90 (m,                                                                      88%)               68  PhCH.sub.2                                                                           ##STR158##                                                                                   ##STR159##    1.92 (s, 3H), 3.67 (s, 2H), 4.98                                              (s, 1H), 5.16 (bs, 2H), 5.35 (dd,                                             1H, J=4.7 and 8.1Hz), 5.52 (d,                                                1H, J=4.7Hz), 6.31 (d, 1H,                                                    J=8.1Hz), 6.75 (s, 1H), 7.1-7.9                                               (m, 18H)           82%                69  PhCH.sub.2                                                                           ##STR160##                                                                                   ##STR161##    1.91 (s, 3H), 2.65 (s, 2H), 3.66                                              (s, 2H), 3.75 (s, 3H), 4.90 (s,                                               1H), 4.96 (s, 1H), 5.07 (s, 2H),                                              5.13 (bs, 1H), 5.28 (dd, 1H,                                                  J=4.8 and 3.1Hz), 5.52 (d, 1H,                                                J=4.8Hz), 6.10 (d, 1H, J=8.1Hz),                                              6.80 (d, 2H, J=8.8Hz), 7.00-7.70                                              (m, 10H)           90%                70  PhCH.sub.2                                                                           ##STR162##                                                                                   ##STR163##    1.91 (s, 3H), 3.66 (s, 2H), 4.90                                              (s, 1H), 4.96 (s, 1H), 5.16 (s,                                               2H), 5.26 (dd, 1H, J=4.0 and                                                  9.0Hz), 5.39 (d, 1H, J=4.0Hz),                                                6.18 (d, 1H, J=9.0Hz), 7.20-7.90                                              (m, 11H), 8.10 (d, 2H,                                                                           89%.0Hz)           71  PhCH.sub.2                                                                           ##STR164##                                                                                   ##STR165##    1.95 (s, 2H), 3.69 (s, 2H), 4.94                                              (s, 1H), 5.02 (s, 1H), 5.15 (s,                                               1H), 5.20-5.60 (m, 4H), 6.31 (d,                                              1H, J=9.0Hz), 7.30-8.10 (m,                                                                      88%)               72  PhOCH.sub.2                                                                          ##STR166##                                                                                   ##STR167##    2.00 (s, 3H), 2.32 (s, 3H), 3.28                                              (bs, 2H), 4.53 (bs, 2H), 5.09                                                 (bs, 1H), 5.24 (bs,                                                           2H), 5.40-5.60 (m, 2H), 6.75-8.00                                             (m, 10H)           79%                73  PhOCH.sub.2                                                                         PhCH.sub.2                                                                                    ##STR168##    1.96 (s, 3H), 4.56 (s, 2H), 4.95                                              (s, 1H), 4.98 (s, 1H), 5.16 (s,                                               2H), 5.42 (dd, 1H, J=4.0 and                                                  7.0Hz), 5.59 (d, 1H, J=4.0Hz),                                                6.65-7.35 (m, 11H), 7.49 (d, 1H,                                              J=8.0Hz), 7.71 (d, 1H, J=8.0Hz),                                              8.05 (s, 1H)       85%                74  PhOCH.sub.2                                                                         PhCH.sub.2                                                                                    ##STR169##    1.94 (s, 3H), 2.63 (s, 3H), 4.46                                              and 4.53 (ABq, 2H, J=13Hz), 4.93                                              (s, 1H), 4.96 (s, 1H), 5.19 (s,                                               3H), 5.43 (dd, 1H, J=4.0 and                                                  8.0Hz), 5.57 (d, 1H, J=4.0Hz),                                                6.75-7.50 (m, 14H) 86%                __________________________________________________________________________

REFERENCE EXAMPLE ##STR170##

Dimethylformamide (0.5 ml) was added to 30 mg of benzyl2-(3-phenylacetamide-4-((1-methyltetrazole-5-yl)thio)-2-azetidinone-1-yl)-3-chloromethyl-3-butenateto obtain a uniform solution. The solution was cooled to -25° C. Theretowas added 40 ml of a about 2M solution of ammonia gas dissolved indimethylformamide and the mixture was stirred for 1 hour. Four drops of5% aqueous solution of hydrochloric acid were added and the mixture wasvigorously agitated to warm to room temperature. The resulting mixturewas diluted with 5 ml of ethyl acetate. The dilute was washed with asaturated aqueous solution of sodium chloride, dried over Na₂ SO₄ andconcentrated. The residue thus obtained was subjected to silica gelcolumn chromatography using a 15:1 benzeneethyl acetate mixture, giving20.8 mg of benzyl7-phenylacetamide-3-((1-methyltetrazole-5-yl)thiomethyl)-3-cephem-4-carboxylate.

The compound thus prepared was chemically analyzed with the followingresult.

IR (nujol): 3265, 1780, 1710, 1655 cm⁻¹.

NMR (CDCl₃): δ(ppm) 3.63 (s, 2H), 3.70 (s, 2H), 3.90 (s, 3H), 4.24 and4.53 (ABq, 2H, 14 Hz), 4.95 (d, 1H, 5 Hz), 5.31 (s, 2H), 5.85 (dd, 1H, 5Hz, 9 Hz), 6.21 (d, 1H, 9 Hz), 7.32 (s, 5H), 7.40 (s, 5H).

We claim:
 1. A process for preparing an azetidinone compound representedby the formula ##STR171## wherein R¹ represents a straight-chain orbranched-chain lower alkyl group, phenyl, p-nitrophenyl, p-chlorophenyl,benzyl, p-nitrophenylmethyl, p-chlorophenylmethyl,p-methoxyphenylmethyl, diphenylmethyl, phenoxymethyl,p-nitrophenoxymethyl or p-chlorophenoxymethyl, R² represents hydrogen,acetyl, propionyl, butyryl, trimethylsilyl, dimethylbutylsilyl,methanesulfonyl, ethanesulfonyl, phenylsulfonyl, p-toluenesulfonyl,diphenylphosphonyl, dibenzylphosphonyl, diethylphosphonyl, or a grouprepresented by the formula ##STR172## wherein R is hydrogen or acarboxyl-protecting group, Z¹ and Z² are the same or different and areeach hydrogen, a halogen, methylthio, ethylthio, phenylthio,p-nitrophenylthio, pentachlorophenylthio, 2-pyridylthio,2-benzothiadiazolylthio, 1,3,4-thiadiazole-5-ylthio,2-substituted-1,3,4-thiadiazole-5 -ylthio, 1,2,3,4-tetrazole-5-ylthio,1-substituted-1,2,3,4-tetrazole-5-ylthio, ethoxythiocarbonylthio,N,N-diethyldithiocarbamate, N,N-dimethyldithiocarbamate, phenylsulfonyl,p-methylphenylsulfonyl, hydroxy, methoxy, ethoxy, acetoxy, benzoyloxy,nitrosoxy, nitryloxy, dimethylamino or piperidine-1-yl, and W is aprotected hydroxyl group, and R³ represents phenyl, p-nitrophenyl,pentachlorophenyl or a group formed by eliminating one hydrogen atomfrom an aromatic heterocyclic compound containing a single heterocyclicring (optionally fused to a benzene ring) of 5-6 members with no morethan 4 heteroatoms selected from the group consisting of nitrogen andsulfur, said aromatic heterocyclic compound optionally having methyl,nitro, methoxy, --CF₃ or phenyl as a substituent, said processcomprising reacting a thiazolinoazetidinone compound represented by theformula ##STR173## wherein R¹ and R² are as defined above with asulphur-containing compound represented by the formula

    R.sup.3 --S--Y                                             (III)

wherein R³ is as defined above and Y represents --SR³ (in which R³ is asdefined above), diethylamino, diisopropylamino, cyclohexylamino,morpholino, piperidino, pyrrolidino, phthalimido or succinimido in thepresence of an acid in a hydrous organic solvent.
 2. A process asdefined in claim 1 in which the compound (III) is used in an amount ofabout 1 to about 10 moles per mole of the compound of the formula (II).3. A process as defined in claim 1 or 2 in which the acid is a mineralacid, sulfonic acid, α-halocarboxylic acid or polycarboxylic acid.
 4. Aprocess as defined in claim 1 or 2 in which the acid is a memberselected from the class consisting of perchloric acid, trifluoroaceticacid, trichloroacetic acid, dichloroacetic acid,trifluoromethanesulfonic acid, trichloromethanesulfonic acid,hydrochloric acid, hydrobromic acid, sulphuric acid, hydrofluoric acid,nitric acid, phosphoric acid, benzenesulfonic acid and toluenesulfonicacid.
 5. A process as defined in any one of claims 1 or 2 in which thecompound of the formual (II) is one wherein R¹ is benzyl, phenoxymethyl,p-chlorophenoxymethyl or phenyl.
 6. A process as defined in any one ofclaims 1 to 5 in which the compound of formula (II) is one wherein R² ishydrogen, ##STR174## (in which R is hydrogen or a carboxyl-protectinggroup, and Z¹ and Z² are the same or different and are each hydrogen,halogen, methylthio, ethylthio, phenylthio, p-nitrophenylthio,pentachlorophenylthio, 2-pyridylthio, 2-benzothiadiazolylthio,1,3,4-thiadiazole-5-ylthio, 2-methyl-1,3,4-thiadiazole-6-ylthio,1,2,3,4-tetrazole-5-ylthio, 1-phenyl-1,2,3,4-tetrazole-5-ylthio,1-methyl-1,2,3,4-tetrazole-5-ylthio, ethoxythiocarbonylthio,N,N-diethyldithiocarbamate, N,N-dimethyldithiocarbamate, phenylsulfonyl,p-methylphenylsulfonyl, hydroxy, methoxy, ethoxy, acetoxy, benzoyloxy,nitrosoxy, nitryloxy, dimethylamino or piperidine-1-yl).
 7. A process asdefined in claim 1 in which the compound of formula (III) is one whereinY is --SR³ (in which R³ is benzothiazolyl-1-yl,5-methyl-1,3,4-thiazolyl-2-yl, 5-phenyl-1,3,4-thiazolyl-2-yl orbenzoimidazolyl-2-yl).
 8. A process as defined in claim 1 wherein R³ isphenyl, p-nitrophenyl, pentachlorophenyl, or a group formed byeliminating one hydrogen atom from an aromatic heterocyclic compoundselected from the group consisting of pyridine, benzimidazole,benzothiazole, tetrazole and thiadiazole, said aromatic heterocycliccompound being optionally substituted with methyl, methoxy, nitro,phenyl or trifluoromethyl.
 9. A process as defined in claim 1 wherein R³is phenyl, p-nitrophenyl, pentachlorophenyl, 2-benzothiazolyl,5-methoxybenzothiazole-2-yl, 5-nitro-benzothioazole-2-yl,5-methylbenzothiazole-2-yl, 5-trifluoromethyl-benzothiazole-2-yl,7-methyl-benzothiazole-2-yl, 2-benzoimidazolyl, 2-pyridyl,1,2,3,4-tetrazole-5-yl, 1-phenyl-1,2,3,4-tetrazole-5-yl,1-methyl-1,2,3,4-tetrazole-5-yl, 2-methyl-1,3,4-thiadiazole-5-yl or2-phenyl-1,3,4-thiadiazole-5-yl.